A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy.

Abstract

Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of nine neurodegenerative disorders that are caused by expansion of polyglutamine-encoding CAG repeats. Intracellular accumulation of abnormal proteins in these diseases, a pathological hallmark, is associated with defects in protein homeostasis. Enhancement of the cellular proteostasis capacity with small molecules has therefore emerged as a promising approach to treatment. Here, we characterize a novel curcumin analog, ASC-JM17, as an activator of central pathways controlling protein folding, degradation and oxidative stress resistance. ASC-JM17 acts on Nrf1, Nrf2 and Hsf1 to increase the expression of proteasome subunits, antioxidant enzymes and molecular chaperones. We show that ASC-JM17 ameliorates toxicity of the mutant androgen receptor (AR) responsible for SBMA in cell, fly and mouse models. Knockdown of the Drosophila Nrf1 and Nrf2 ortholog cap 'n' collar isoform-C, but not Hsf1, blocks the protective effect of ASC-JM17 on mutant AR-induced eye degeneration in flies. Our observations indicate that activation of the Nrf1/Nrf2 pathway is a viable option for pharmacological intervention in SBMA and potentially other polyglutamine diseases.

• Authors: Laura C Bott, Nisha M Badders, Ke-Lian Chen, George G Harmison, Elaine Bautista, Charles C-Y Shih, Masahisa Katsuno, Gen Sobue, J Paul Taylor, Nico P Dantuma, Kenneth H Fischbeck, Carlo Rinaldi
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 25 Issue 10 Pg. 1979-1989 (05 15 2016) ISSN: 1460-2083 [Electronic] England
• PMID: 26962150 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Intramural, Research Support, N.I.H., Extramural)
• Copyright: Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Chemical References

• AR protein, human
• ASC-JM17
• DNA-Binding Proteins
• Drosophila Proteins
• Heat Shock Transcription Factors
• Hsf protein, Drosophila
• NF-E2-Related Factor 1
• NF-E2-Related Factor 2
• Peptides
• Receptors, Androgen
• Small Molecule Libraries
• Transcription Factors
• polyglutamine
• Proteasome Endopeptidase Complex
• Curcumin

Topics

• Animals
• Bulbo-Spinal Atrophy, X-Linked (drug therapy, genetics, pathology)
• Curcumin (administration & dosage, analogs & derivatives, chemistry)
• DNA-Binding Proteins (genetics)
• Disease Models, Animal
• Drosophila Proteins (genetics)
• Drosophila melanogaster (genetics)
• Gene Knockdown Techniques
• Heat Shock Transcription Factors
• Humans
• Mice
• Muscular Disorders, Atrophic (drug therapy, genetics, pathology)
• NF-E2-Related Factor 1 (genetics)
• NF-E2-Related Factor 2 (genetics)
• Oxidative Stress (drug effects)
• Peptides (genetics)
• Proteasome Endopeptidase Complex (drug effects)
• Protein Aggregation, Pathological (genetics)
• Protein Folding (drug effects)
• Receptors, Androgen (genetics)
• Signal Transduction (drug effects)
• Small Molecule Libraries (administration & dosage)
• Transcription Factors (genetics)
• Trinucleotide Repeat Expansion (genetics)